EMTRICITABINE/TENOFOVIR DISOPROXIL KRKA D.D.

d. should be initiated by a physician experienced in the management of HIV infection.

Posology Adults and adolescents aged 12 years and older, weighing at least 35 kg:

One tablet, once daily. d.. Please refer to the Summary of Product Characteristics for these medicinal products. d. d. should be taken as soon as possible and the normal dosing schedule should be resumed. d. is missed by more than 12 hours and it is almost time for the next dose, the missed dose should not be taken and the usual dosing schedule should be resumed.

, another tablet should be taken. d. a second dose should not be taken. 2). 2). d. should only be used in individuals with creatinine clearance (CrCl) <80 mL/min if the potential benefits are considered to outweigh the potential risks. See Table 1.

4). 4). Severe renal impairment (CrCl < 30 mL/min) and haemodialysis patients Not recommended because appropriate dose reductions cannot be achieved with the combination tablet. 4). 2). 2). Method of administration Oral administration. d.

is taken with food. The film-coated tablet can be disintegrated in approximately 100 mL of water, orange juice or grape juice and taken immediately.

1). The safety profile of emtricitabine and tenofovir disoproxil in this study was consistent with the previous experience with these agents when each was administered with other antiretroviral agents. Tabulated summary of adverse reactions The adverse reactions considered at least possibly related to treatment with the tenofovir disoproxil and emtricitabine from clinical study and post-marketing experience in HIV-1 infected patients are listed in Table 3, below, by body system organ class and frequency.

Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness. Frequencies are defined as very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1 000 to < 1/100) or rare (≥ 1/10 000 to < 1/1 000).

Table 3:

Tabulated summary of adverse reactions associated with tenofovir disoproxil and emtricitabine based on clinical study and post-marketing experience Frequency Emtricitabine Tenofovir disoproxil Blood and lymphatic system disorders: Common: neutropenia Uncommon: anaemia2 Immune system disorders: Common: allergic reaction Metabolism and nutrition disorders: Very common: hypophosphataemia1 Common: hyperglycaemia, hypertriglyceridaemia Uncommon: hypokalaemia1 Rare: lactic acidosis Psychiatric disorders: Common: insomnia, abnormal dreams Nervous system disorders: Very common: headache dizziness Common: dizziness headache Gastrointestinal disorders: Very common: diarrhoea, nausea diarrhoea, vomiting, nausea Common: elevated amylase including elevated pancreatic amylase, elevated serum lipase, vomiting, abdominal pain, dyspepsia abdominal pain, abdominal distension, flatulence Uncommon: pancreatitis Hepatobiliary disorders: Common: elevated serum aspartate aminotransferase (AST) and/or elevated serum alanine aminotransferase (ALT), hyperbilirubinaemia increased transaminases Rare: hepatic steatosis, hepatitis Skin and subcutaneous tissue disorders: Very common: rash Common: vesiculobullous rash, pustular rash, maculopapular rash, rash, pruritus, urticaria, skin discolouration (increased pigmentation)2 Uncommon: angioedema3 Rare: angioedema Musculoskeletal and connective tissue disorders: Very common: elevated creatine kinase Common bone mineral density decreased Uncommon: rhabdomyolysis1, muscular weakness1 Rare: osteomalacia (manifested as bone pain and infrequently contributing to fractures)1,3, myopathy1 Renal and urinary disorders: Uncommon: increased creatinine, proteinuria, proximal renal tubulopathy including Fanconi syndrome Rare: renal failure (acute and chronic), acute tubular necrosis, nephritis (including acute interstitial nephritis)3, nephrogenic diabetes insipidus General disorders and administration site conditions: Very common: asthenia Common: pain, asthenia 1 This adverse reaction may occur as a consequence of proximal renal tubulopathy.

It is not considered to be causally associated with tenofovir disoproxil in the absence of this condition. 2 Anaemia was common and skin discolouration (increased pigmentation) was very common when emtricitabine was administered to paediatric patients.

3 This adverse reaction was identified through post-marketing surveillance but not observed in randomised controlled clinical studies in adults or paediatric HIV clinical studies for emtricitabine or in randomised controlled clinical studies or the tenofovir disoproxil expanded access program for tenofovir disoproxil.

The frequency category was estimated from a statistical calculation based on the total number of patients exposed to emtricitabine in randomised controlled clinical studies (n = 1,563) or tenofovir disoproxil in randomised controlled clinical studies and the expanded access program (n = 7,319).

d. 4). Proximal renal tubulopathy generally resolved or improved after tenofovir disoproxil discontinuation. However, in some HIV- 1 infected patients, declines in creatinine clearance did not completely resolve despite tenofovir disoproxil discontinuation.

4).

Lactic acidosis:

Cases of lactic acidosis have been reported with tenofovir disoproxil alone or in combination with other antiretrovirals. Patients with predisposing factors such as patients with decompensated liver disease, or patients receiving concomitant medications known to induce lactic acidosis are at increased risk of experiencing severe lactic acidosis during tenofovir disoproxil treatment, including fatal outcomes.

4).

Immune Reactivation Syndrome:

In HIV infected patients with severe immune deficiency at the time of initiation of CART, an inflammatory reaction to asymptomatic or residual opportunistic infections may arise. 4).

Osteonecrosis:

Cases of osteonecrosis have been reported, particularly in patients with generally acknowledged risk factors, advanced HIV disease or long-term exposure to CART. 4). Paediatric […]

d. 1). Patients with hepatitis B or C virus infection HIV-1 infected patients with chronic hepatitis B or C treated with antiretroviral therapy are at an increased risk for severe and potentially fatal hepatic adverse reactions. Physicians should refer to current HIV treatment guidelines for the management of HIV infection in patients co-infected with hepatitis B virus (HBV) or hepatitis C virus (HCV).

In case of concomitant antiviral therapy for hepatitis B or C, please refer also to the relevant Summary of Product Characteristics for these medicinal products. See also under Use with ledipasvir and sofosbuvir or sofosbuvir and velpatasvir below.

Tenofovir disoproxil is indicated for the treatment of HBV and emtricitabine has shown activity against HBV in pharmacodynamic studies but the safety and efficacy of emtricitabine/tenofovir disoproxil have not been specifically established in patients with chronic HBV infection.

d. therapy in patients infected with HBV may be associated with severe acute exacerbations of hepatitis. d. should be closely monitored with both clinical and laboratory follow-up for at least several months after stopping treatment. If appropriate, resumption of hepatitis B therapy may be warranted.

In patients with advanced liver disease or cirrhosis, treatment discontinuation is not recommended since post-treatment exacerbation of hepatitis may lead to hepatic decompensation. Liver disease The safety and efficacy of emtricitabine/tenofovir disoproxil have not been established in patients with significant underlying liver disorders.

The pharmacokinetics of tenofovir has been studied in patients with hepatic impairment and no dose adjustment is required. The pharmacokinetics of emtricitabine has not been studied in patients with hepatic impairment. d. 2). HIV-1infected patients with pre-existing liver dysfunction, including chronic active hepatitis, have an increased frequency of liver function abnormalities during combination antiretroviral therapy (CART) and should be monitored according to standard practice.

If there is evidence of worsening liver disease in such patients, interruption or discontinuation of treatment must be considered. Renal and bone effects in adults Renal effects Emtricitabine and tenofovir are primarily excreted by the kidneys by a combination of glomerular filtration and active tubular secretion.

8). d. for the treatment of HIV-1 infection, it is recommended that creatinine clearance is calculated in all individuals. In individuals without risk factors for renal disease, it is recommended that renal function (creatinine clearance and serum phosphate) is monitored after two to four weeks of use, after three months of use and every three to six months thereafter.

In individuals at risk for renal disease more frequent monitoring of renal function is required. See also under Co-administration of other medicinal products below. 8, proximal tubulopathy). d. 32 mmol/L). d. should also be considered in case of progressive decline of renal function when no other cause has been identified.

Renal safety with emtricitabine/tenofovir disoproxil has only been studied to a very limited degree in HIV-1 infected patients with impaired renal function (creatinine clearance < 80 mL/min). 2). Limited clinical study data suggest that the prolonged dose interval is not optimal and could result in increased toxicity and possibly inadequate response.

2). d. is used in patients with creatinine clearance < 60 mL/min, and renal function should be closely monitored. d. at a prolonged dosing interval. d. is not recommended in patients with severe renal impairment (creatinine clearance < 30 mL/min) and in patients who require haemodialysis since appropriate dose reductions cannot […]

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